Investigation of sex-specific effects of apolipoprotein E on severity of EAE and MS

Abstract

BackgroundDespite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS.MethodsMOG35-55 induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses.ResultsEAE disease course was slightly attenuated in male apoE-deficient (apoE−/−) mice compared to wildtype mice (cumulative median score: apoE−/− = 2 [IQR 0.0–4.5]; wildtype = 4 [IQR 1.0–5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE−/− mice compared to wildtype mice (cumulative median score: apoE−/− = 3 [IQR 2.0–4.5]; wildtype = 3 [IQR 0.0–4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex.ConclusionsapoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0429-y) contains supplementary material, which is available to authorized users.

Serum Lipoprotein Profile Is Associated With Protective Effects of Oral Contraceptive Use on Multiple Sclerosis Severity: A Cross-Sectional Study

“…Nevertheless, results are mixed, and whether these relations are causal or secondary to the disease process, treatment regimens or other confounding factors remain uncertain. Complex interactions between cholesterol metabolism and sex steroids are well-known (3) and may modulate the clinical activity of experimental autoimmune encephalomyelitis (EAE), the animal model for MS (4, 5). Therefore, we hypothesized that the putative associations between lipoprotein metabolism and the severity of MS could be modulated by sex hormone exposure.…”

Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis

“…However, it is worth noting that the association of the HLA genetic burden score reported by Isobe et al 14 was also not replicated in our larger German genetics cohort. 36 Regarding the role of APOE in MS course, genetic association results have overall been largely contradictory, [15][16][17][18][19][20] suggesting that the functional APOE variants rs429358 and rs7412 do not play a major role in defining MS severity. Along these lines, our current study may support this notion.…”

“…However, results have been contradictory. [15][16][17][18][19][20] Most studies have investigated these factors in the context of long-term disease progression. 8,16,18 The role of any of these factors in early disease progression remains unclear.…”

Metabolic Dysfunction and Peroxisome Proliferator-Activated Receptors (PPAR) in Multiple Sclerosis

“…During the last few decades, the concept of MS pathogenesis was profoundly influenced by research conducted in experimental autoimmune encephalomyelitis (EAE). These animal models mimic many pathological aspects and all clinical forms of MS [ 6 , 7 , 8 ]. This has led many authors to suggest that MS has a primary autoimmune etiology.…”

“…The Mailleux group also reported that in EAE, LDL receptor deficiency attenuates the severity of the disease in females (not in males) mice, through the induction of ApoE [ 65 ]. Interestingly, other authors have found that, in ApoE knock-out mice, ApoE deficiency increases EAE severity only in female animals [ 8 ]. These findings suggest interactions between sex steroids and cholesterol metabolism in the development of CNS lesions and severity of the disease.…”